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FERNE/EMRA ICH Pathophysiology: ICH Pathophysiology: Key Concepts for the Key Concepts for the Emergency Physician Emergency Physician

FERNE/EMRA ICH Pathophysiology: Key Concepts for the Emergency Physician

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Page 1: FERNE/EMRA ICH Pathophysiology: Key Concepts for the Emergency Physician

FERNE/EMRA

ICH Pathophysiology:ICH Pathophysiology:Key Concepts for the Key Concepts for the Emergency PhysicianEmergency Physician

Page 2: FERNE/EMRA ICH Pathophysiology: Key Concepts for the Emergency Physician

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Marc Dorfman, MD, FACEP, Marc Dorfman, MD, FACEP, MACPMACP

EM Residency Program DirectorEM Residency Program Director

Resurrection Medical CenterResurrection Medical CenterChicago, ILChicago, IL

Marc Dorfman, MD, FACEP, MACP

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ICH Hemorrhage ICH Hemorrhage VolumeVolume

ICH Hemorrhage ICH Hemorrhage VolumeVolume

• Old concept- Hemorrhage is static process; Old concept- Hemorrhage is static process; bleeding complete in a minutesbleeding complete in a minutes

• New concept- Hemorrhage is dynamic; New concept- Hemorrhage is dynamic; process continues for several hoursprocess continues for several hours

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ICH Volume and ICH Volume and OutcomeOutcome

ICH Volume and ICH Volume and OutcomeOutcome

• Broderick: 1993 StrokeBroderick: 1993 Stroke• Goals: “to determine the most important predictors Goals: “to determine the most important predictors

of morbidity and mortality…in the treatment of of morbidity and mortality…in the treatment of intracerebral hemorrhage.”intracerebral hemorrhage.”

• Methods: 188 cases, retrospective reviewMethods: 188 cases, retrospective review• ““We report a study of the natural history of We report a study of the natural history of

intracerebral hemorrhage in the 1.26 million intracerebral hemorrhage in the 1.26 million metropolitan population of Greater Cincinnati” metropolitan population of Greater Cincinnati”

• Study funded by the American Heart AssociationStudy funded by the American Heart Association

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ICH Volume and ICH Volume and OutcomeOutcome

ICH Volume and ICH Volume and OutcomeOutcome

• Results: Results: • 162 cases (26 excluded-lost CT, autopsy, IVH 162 cases (26 excluded-lost CT, autopsy, IVH

alone))alone))• Mortality 44% with half in first 2 daysMortality 44% with half in first 2 days

• Key Concept:Key Concept:• Volume of parenchyma hemorrhage was the Volume of parenchyma hemorrhage was the

most important predictor of 30-day survival for most important predictor of 30-day survival for all ages and locations of hemorrhagesall ages and locations of hemorrhages

• Initial Glasgow Coma Scale was also Initial Glasgow Coma Scale was also significant predictor of 30 day mortalitysignificant predictor of 30 day mortality

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PrognosisPrognosisPrognosisPrognosis• WorseWorse

• Volume > 60 cmVolume > 60 cm33 and GCS < 9 and GCS < 9• 91% dead at 30 days91% dead at 30 days

• Patients with > 30 cmPatients with > 30 cm3 3

• Only 1/71 independent at 30 daysOnly 1/71 independent at 30 days• Other: age, seizures, intraventricular extensionOther: age, seizures, intraventricular extension

• BetterBetter• Volume < 30 cmVolume < 30 cm33 and GCS 9 or higher and GCS 9 or higher

• 19% dead at 30 days 19% dead at 30 days

(Broderick, Stroke 1993;24:987- 93)

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Hematoma VolumeHematoma VolumeHematoma VolumeHematoma Volume• Formula for volume of an ellipsoidFormula for volume of an ellipsoid

• 4/34/3ππ (A/2)(B/2)(C/2) (A/2)(B/2)(C/2)• Simplified A*B*C / 2Simplified A*B*C / 2

A

B

C

A-greatest hemorrhage A-greatest hemorrhage diameter diameter B-diameter 90 degrees to AB-diameter 90 degrees to AC-approximate number of CT C-approximate number of CT slices with hemorrhage slices with hemorrhage multiplied by slice thickness multiplied by slice thickness in cmin cm

Page 9: FERNE/EMRA ICH Pathophysiology: Key Concepts for the Emergency Physician

FERNE/EMRABroderick, Stroke 1993;24:987- 93)

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ICH Volume GrowthICH Volume GrowthICH Volume GrowthICH Volume Growth

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Early Hemorrhage Early Hemorrhage GrowthGrowth

Early Hemorrhage Early Hemorrhage GrowthGrowth

• Stroke, 1997Stroke, 1997• Goals: To prospectively determine how Goals: To prospectively determine how

frequently early growth in intracerebral frequently early growth in intracerebral hemorrhage occurs and whether this hemorrhage occurs and whether this early growth is related to neurological early growth is related to neurological deteriorationdeterioration

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ICH Growth Study ICH Growth Study DesignDesign

ICH Growth Study ICH Growth Study DesignDesign

• 103 patients (39 patients excluded-103 patients (39 patients excluded-incomplete CT, Anticoag, vascular incomplete CT, Anticoag, vascular abnorm)abnorm)

• CT scan baseline 1 and 20 hoursCT scan baseline 1 and 20 hours• Positive-increase hemorrhage 33%Positive-increase hemorrhage 33%• 38% patients with > 33% growth in 38% patients with > 33% growth in

volume of parenchyma hemorrhagevolume of parenchyma hemorrhage

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ICH ProgressionICH ProgressionICH ProgressionICH Progression

• Symptoms often progress, Symptoms often progress, associated with ICH growthassociated with ICH growth

• 2/3 with progression of symptoms 2/3 with progression of symptoms • 1/3 maximal at onset1/3 maximal at onset

• Within hours from onset:Within hours from onset:• 26% with >33% growth in next 126% with >33% growth in next 1oo

• 12% with >33% growth 1-2012% with >33% growth 1-20oo

(Brott, Stroke 1997;28:1-5)

2.0 hours after onset

6.5 hours after onset

2.0 hours after onset

6.5 hours after onset

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28 mL

43 mL

(Image courtesy T. Brott, MD)

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Safety Factor FVIIa in Safety Factor FVIIa in ICHICH

Safety Factor FVIIa in Safety Factor FVIIa in ICHICH

• Mayer: 2005 Stroke Phase II trialMayer: 2005 Stroke Phase II trial• Goals: Hematoma growth occurs in 38% of ICHGoals: Hematoma growth occurs in 38% of ICH• Key Concept: FVIIa is safe when given within 3 Key Concept: FVIIa is safe when given within 3

hours of presentationhours of presentation• Data: 48 patients, 6 doses testedData: 48 patients, 6 doses tested• Data: No safety issues preclude phase IIIData: No safety issues preclude phase III• Implications: Larger study is justified, given Implications: Larger study is justified, given

data on hemorrhage volume growth and data on hemorrhage volume growth and outcomeoutcome

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FVIIa Safety, Efficacy in FVIIa Safety, Efficacy in ICHICH

FVIIa Safety, Efficacy in FVIIa Safety, Efficacy in ICHICH

• Mayer: 2005 NEJMMayer: 2005 NEJM• Key Concept: FVIIa is safe when given within 3 Key Concept: FVIIa is safe when given within 3

hours of presentationhours of presentation• Data: 399 pts, 3 doses, ICH growth, 90-dayData: 399 pts, 3 doses, ICH growth, 90-day• Data: Less ICH growth, improved outcomeData: Less ICH growth, improved outcome• Data: Thromboembolic events notedData: Thromboembolic events noted• Implications: Larger study is critical in order to Implications: Larger study is critical in order to

establish clear benefit, safetyestablish clear benefit, safety

Study supported by Novo Nordisk

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Factor VIIaFactor VIIaFactor VIIaFactor VIIa• Placebo, 40, 80, 160 mcg/kg F-VIIaPlacebo, 40, 80, 160 mcg/kg F-VIIa• 38% relative reduction in mortality38% relative reduction in mortality• 11% absolute mortality reduction 11% absolute mortality reduction • Double the odds of improvement by one Double the odds of improvement by one

level on the modified Rankin scale at 90 level on the modified Rankin scale at 90 daysdays

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Exclusion CriteriaExclusion CriteriaExclusion CriteriaExclusion Criteria• GCS 3-5GCS 3-5• Planned surgical Planned surgical

evacuationevacuation• Aneurysm, AV Aneurysm, AV

malformation, trauma malformation, trauma or other causeor other cause

• Oral anticoagulantsOral anticoagulants• Acute sepsisAcute sepsis

• Crush injuryCrush injury• DICDIC• PregnancyPregnancy• Pre-existing disabilityPre-existing disability• Symptomatic vaso-Symptomatic vaso-

occlusive disease occlusive disease (angina, claudication, (angina, claudication, DVT, CVA, MI) within 30 DVT, CVA, MI) within 30 days before the ICHdays before the ICH

Midway through the trial, symptomatic vaso-occlusive disease was amended to exclude patients with any history of thrombotic or vaso-occlusive disease

Page 22: FERNE/EMRA ICH Pathophysiology: Key Concepts for the Emergency Physician

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Factor VIIFactor VIIFactor VIIFactor VII• Serious thromboembolic adverse events, Serious thromboembolic adverse events,

mainly myocardial infarction or cerebral mainly myocardial infarction or cerebral infarction occurred in 7 percent of the F-infarction occurred in 7 percent of the F-VIIa treated patients, as compared with 2 VIIa treated patients, as compared with 2 percent of those given placebopercent of those given placebo

• Number needed to benefit is 9Number needed to benefit is 9• Number needed to harm is 20Number needed to harm is 20

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Functional Outcome Functional Outcome ScalesScales

Functional Outcome Functional Outcome ScalesScales

• Modified Rankin scale (mRS)Modified Rankin scale (mRS)• Barthel Index (BI)Barthel Index (BI)• Glasgow Outcome Scale (GOS)Glasgow Outcome Scale (GOS)• Utilize scored assessments of patient’s Utilize scored assessments of patient’s

functional statusfunctional status• Can be used to gauge:Can be used to gauge:

• pre-morbid baseline pre-morbid baseline • outcomeoutcome

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ScoreScore DescriptionDescription

66 DeadDead

55 Severe disabilitySevere disability: bedridden, incontinent, and requiring constant nursing : bedridden, incontinent, and requiring constant nursing care and attentioncare and attention

44 Moderately severe disabilityModerately severe disability: unable to walk without assistance and : unable to walk without assistance and unable to attend to own bodily needs without assistanceunable to attend to own bodily needs without assistance

33 Moderate disabilityModerate disability: requiring some help, but able to walk without : requiring some help, but able to walk without assistanceassistance

22 Slight disabilitySlight disability: unable to carry out all previous activities, but able to look : unable to carry out all previous activities, but able to look after own affairs without assistanceafter own affairs without assistance

11 No significant disabilityNo significant disability: despite symptoms, able to carry out all usual : despite symptoms, able to carry out all usual duties and activitiesduties and activities

00 No symptoms at allNo symptoms at all

Modified Rankin ScaleModified Rankin ScaleModified Rankin ScaleModified Rankin Scale

Good outcome = score of 0 - 1

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Factor VIIFactor VIIFactor VIIFactor VII• The FDA will not approve label indication for The FDA will not approve label indication for

F-VIIa for acute ICH until safety and F-VIIa for acute ICH until safety and potential dose-response issues are clarifiedpotential dose-response issues are clarified

• Pending completion of the ongoing phase III Pending completion of the ongoing phase III trial, we do not recommend use of Factor trial, we do not recommend use of Factor VIIa outside of a clinical trial protocolVIIa outside of a clinical trial protocol

• Cost is $1020-$1369 per 1.2 mg vialCost is $1020-$1369 per 1.2 mg vial

Modern Treatment Options for Intracerebral Hemorrhage; Freeman, Brott, Critical Care Neurology; 2006 8:145-157

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FVIIa Adverse FVIIa Adverse EventsEvents

FVIIa Adverse FVIIa Adverse EventsEvents

• O’Connell JAMA 2006; 295:293-298O’Connell JAMA 2006; 295:293-298• Adverse events reported to the FDAAdverse events reported to the FDA• 1999-20041999-2004• 431 reported, 185 thrombo-embolic431 reported, 185 thrombo-embolic• 39 CVA, 34 MI, 32 PE, 26 Art. Thrombus39 CVA, 34 MI, 32 PE, 26 Art. Thrombus• 52% occur in the first 24 hours52% occur in the first 24 hours• Thromboembolic AE’s follow off label useThromboembolic AE’s follow off label use

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TPA vs. Factor VIIaTPA vs. Factor VIIaTPA vs. Factor VIIaTPA vs. Factor VIIa• TPA-risk is bleedingTPA-risk is bleeding• Factor VIIa-risk is clotting in at Factor VIIa-risk is clotting in at

risk vascular beds (Cardiac, risk vascular beds (Cardiac, Cerebral, DVT, etc)Cerebral, DVT, etc)